U.S. patent number 4,110,429 [Application Number 05/755,895] was granted by the patent office on 1978-08-29 for antibacterial oral composition.
This patent grant is currently assigned to Colgate-Palmolive Company. Invention is credited to Stuart D. Friedman, Abdul Gaffar.
United States Patent |
4,110,429 |
Gaffar , et al. |
August 29, 1978 |
Antibacterial oral composition
Abstract
An antibacterial oral composition effective to promote oral
hygiene containing an antibacterial antiplaque agent and an
additive which reduces staining of dental surfaces without
substantially diminishing the antibacterial and antiplaque activity
of the agent. Bis-biguanido hexanes, such as chlorhexidine and
alexidine, and quaternary ammonium salts, such as benzethonium
chloride and cetyl pyridinium chloride are typical examples of
antibacterial agents. The antistain additive is a water soluble
oligomer of the formula ##STR1## wherein M is a water soluble
orally acceptable cation; R.sub.1, r.sub.2, r.sub.3 and R.sub.4 are
independently H, methyl or ethyl; Y is at least one hydrophilic
member of the group consisting of --COOM.sub.1, --CONH.sub.2, and
--CH.sub.2 OH; X is at least one hydrophobic member of the group
consisting of --CN, --COOR, --COOR.sub.5 OR, --CONHR,
--COONHR.sub.5 COR, and --OOCR; M.sub.1 is H or M; R is C.sub.1-8
alkyl; R.sub.5 is C.sub.1-4 alkylene; a is 0-7; and a+b is about
4-15.
Inventors: |
Gaffar; Abdul (Somerset,
NJ), Friedman; Stuart D. (Bound Brook, NJ) |
Assignee: |
Colgate-Palmolive Company (New
York, NY)
|
Family
ID: |
25041127 |
Appl.
No.: |
05/755,895 |
Filed: |
December 30, 1976 |
Current U.S.
Class: |
424/54 |
Current CPC
Class: |
A61K
8/416 (20130101); A61K 8/43 (20130101); A61K
8/8147 (20130101); A61Q 11/00 (20130101) |
Current International
Class: |
A61K
8/41 (20060101); A61K 8/43 (20060101); A61K
8/72 (20060101); A61K 8/81 (20060101); A61K
8/30 (20060101); A61Q 11/00 (20060101); A61K
017/22 () |
Field of
Search: |
;424/54 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Chem. Abstr. 72 #112506n of Dannals U.S. 3,498,943 (1970)
(Oligomers as Emulsifiers). .
Chem. Abstr. 72 #101646g of Dannals et al. Fr. 1,521,995 (1970)
(Oligomers Useful as Surfactants, Emulsifiers)..
|
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Sylvester; Herbert S. Grill; Murray
M. Stone; Robert L.
Claims
What is claimed is:
1. An oral composition comprising an oral vehicle, at least one
nitrogen-containing antibacterial antiplaque agent, whose use has
been observed to lead to staining or discoloration of dental
surfaces, selected from the group consisting of cationic
antibacterial antiplaque agent and long chain amine antibacterial
antiplaque agent containing a fatty alkyl group of about 12 to 18
carbon atoms and as an anti-staining additive, present in a molar
ratio, relative to said agent, of about 0.2:1 to about 6:1, of at
least one water soluble oligomer of the formula ##STR7## wherein M
is a water soluble orally acceptable cation;
R.sub.1,r.sub.2,r.sub.3 and R.sub.4 are independently H, methyl or
ethyl;
Y is at least one hydrophilic member of the group consisting of
--COOM.sub.1, --CONH.sub.2, and --CH.sub.2 OH;
X is at least one hydrophobic member of the group consisting of
--CN, --COOR.sub.5 OR, --CONHR, --COONHR.sub.5 COR, and --OOCR;
M.sub.1 is H or M;
R is C.sub.1-8 alkyl;
R.sub.5 is C.sub.1-4 alkylene;
a is 0-7; and
a+b is about 4-15.
2. The oral composition of claim 1 wherein said antibacterial
antiplaque agent is present in an amount to provide about 0.001 to
about 15% by weight based on the free base form of said agent and
said oligomer is present in amount of about 0.01 to about 10% by
weight.
3. The oral composition of claim 2 wherein said antibacterial
antiplaque agent is present in an amount of about 0.01 to about 5%
by weight, based on its free base form.
4. The oral composition of claim 2 wherein said antibacterial
antiplaque agent is a substituted guanidine.
5. The oral composition of claim 4 wherein said antibacterial
antiplaque agent is a pharmaceutically acceptable water soluble
salt of an agent selected from the group consisting of
chlorhexidine and alexidine.
6. The oral composition of claim 5 wherein said antibacterial
antiplaque agent is a pharmaceutically acceptable water soluble
salt of chlorhexidine.
7. The oral composition of claim 2 wherein said antibacterial
antiplaque agent is benzethonium chloride.
8. The oral composition of claim 2 wherein said antibacterial
antiplaque agent is a quaternary ammonium compound containing 1 to
2 alkyl groups of 8 to 20 carbon atoms.
9. The oral composition of claim 8 wherein said antibacterial
antiplaque agent is cetyl pyridinium chloride.
10. The oral composition of claim 1 wherein, in said formula, a is
zero, a+b is about 10, Y is --COOM.sub.1, R.sub.1, R.sub.2, R.sub.3
and R.sub.4 are H, and M and M.sub.1 are sodium.
11. The oral composition of claim 1 wherein said vehicle is an
aqueous-alcohol and said composition is a mouthwash of pH of about
4.5 to about 9.
12. The oral composition of claim 1 wherein said vehicle comprises
a liquid vehicle and a gelling agent and a dentally acceptable
polishing material is present and said composition is a toothpaste
of pH of about 4.5 to about 9.
13. The mouthwash composition of claim 11 containing about 0.01 to
about 5.0% by weight, based on its free base form, of benzethonium
chloride.
14. The mouthwash composition of claim 11 containing about 0.01 to
about 5% by weight, based on its free base form, of a water-soluble
pharmaceutically acceptable salt of chlorhexidine.
15. A method of preparing an oral composition as defined in claim 1
wherein said oligomer is added to the remaining components of said
composition after said components have been contacted with each
other.
16. A method of improving oral hygiene comprising applying to the
oral cavity an effective amount of an oral composition as defined
in claim 1.
Description
This invention relates to an antibacterial oral composition which
promotes oral hygiene.
Cationic nitrogen-containing antibacterial materials are well known
in the art. See, for instance the section on "Quaternary Ammonium
and Related Compounds" in the article on "Antiseptics and
Disinfectants" in Kirk-Othmer Encyclopedia of Chemical Technology,
second edition (Vol. 2, p. 632-635), incorporated herein by
reference. Cationic materials which possess antibacterial activity
(i.e. are germicides) are used against bacteria and have been used
in oral compositions to counter plaque formation caused by bacteria
in the oral cavity.
Among the most common of these antibacterial antiplaque quaternary
ammonium compounds is benzethonium chloride, also known as Hyamine
1622 or diisobutylphenoxyethoxyethyl dimethyl benzyl ammonium
chloride. In an oral preparation this material is highly effective
in promoting oral hygiene by reducing formation of dental plaque
and calculus, which is generally accompanied by a reduction in
caries formation and periodontal diseases. Other cationic
antibacterial agents of this type are those mentioned, for
instance, in U.S. Pat. Nos. 2,984,639, 3,325,402, 3,431,208 and
3,703,583, and British Pat. No. 1,319,396.
Other antibacterial antiplaque quaternary ammonium compounds
include those in which one or two of the substituents on the
quaternary nitrogen has a carbon chain length (typically alkyl
group) of some 8 to 20, typically 10 to 18, carbon atoms while the
remaining substituents have a lower number of carbon atoms
(typically alkyl or benzyl group), such as 1 to 7 carbon atoms,
typically methyl or ethyl groups. Dodecyl trimethyl ammonium
bromide, dodecyl dimethyl (2-phenoxyethyl) ammonium bromide, benzyl
dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and
quaternized 5-amino-1,3-bis (2-ethyl-hexyl)-5-methyl hexa
hydropyrimidine are exemplary of other typical quaternary ammonium
antibacterial agents.
Other types of cationic antibacterial agents which are desirably
incorporated in oral compositions to promote oral hygiene by
reducing plaque formation are the amidines such as the substituted
guanidines e.g. chlorhexidine and the corresponding compound,
alexidine, having 2-ethylhexyl groups instead of chlorophenyl
groups and other bis-biguanides such as those described in German
patent application No. P 2,332,383 published Jan. 10, 1974, which
sets forth the following formula: ##STR2## in which A and A'
signify as the case may be either (1) a phenyl radical, which as
substituent can contain up to 2 alkyl or alkoxy groups with 1 up to
about 4C-atoms, a nitro group or a halogen atom, (2) an alkyl group
which contains 1 to about 12C-atoms, or (3) alicyclic groups with 4
to about 12C-atoms, X and X' as the case may be may represent an
alkylene radical with 1-3C atoms, z and z' are as the case may be
either zero or 1, R and R' as the case may be may represent either
hydrogen, an alkyl radical with 1 to about 12C-atoms or an aralkyl
radical with 7 to about 12C-atoms, n is a whole number of 2 to
inclusively 12 and the polymethylene chain (CH.sub.2) can be
interrupted by up to 5 ether, thioether, phenyl- or naphthyl
groups; these are available as pharmaceutically suitable salts.
Additional substituted guanidines are: N'-(4-chlorobenzyl)-N.sup.5
-(2,4-dichlorobenzyl) biguanide; p-chlorobenzyl biguanide,
4-chlorobenzhydryl guanylurea; N-3-lauroxypropyl-N.sup.5
-p-chlorobenzyl biguanide; 5,6-dichloro-2-guanidobenzimidazole; and
N-p-chlorophenyl-N.sup.5 -laurylbiguanide.
The long chain tertiary amines also possess antibacterial and
antiplaque activity. Such antibacterial agents include tertiary
amines having one fatty alkyl group (typically 12 to 18 carbon
atoms) and 2 poly(oxyethylene) groups attached to the nitrogen
(typically containing a total of from 2 to 50 ethenoxy groups per
molecule) and salts thereof with acids and compounds of the
structure: ##STR3## where R is a fatty alkyl group containing 12 to
18 carbon atoms and x, y and z total 3 or higher, as well as salts
thereof. Generally, cationic agents are preferred for their
antiplaque effectiveness.
The antibacterial antiplaque compound is preferably one which has
an antibacterial activity such that its phenol co-efficient is well
over 50, more preferably well above 100, such as above about 200 or
more for S. aureus; for instance the phenol coefficient (A.O.A.C.)
of benzethonium chloride is given by the manufacturer as 410, for
S. aureus. The cationic antibacterial agent will generally be a
monomeric (or possibly dimeric) material molecular weight well
below 2,000, such as less than about 1,000. It is, however, within
the broader scope of the invention to employ a polymeric cationic
antibacteria agent. The cationic antibacterial is preferably
supplied in the form of an orally acceptable salt thereof, such as
the chloride, bromide, sulfate, alkyl sulfonate such as methyl
sulfonate and ethyl sulfonate, phenylsulfonate, such as
p-methylphenyl sulfonate, nitrate, acetate, gluconate, etc.
The nitrogen-containing cationic antibacterial agents and long
chain tertiary amine antibacterial agents effectively promote oral
hygiene, particularly by removing plaque. However, their use has
been observed to lead to staining of dental surfaces or
discoloration.
The reason for the formation of such dental stain has not been
clearly established. However, human dental enamel contains a high
proportion (about 95%) of hydroxyapatite (HAP) which includes
Ca.sup.+2 and PO.sub.4.sup.-3 ions. In the absence of dental plaque
additional Ca.sup.+2 and PO.sub.4.sup.-3, particularly from saliva,
can be deposited on the enamel and such deposits can include color
bodies which ultimately stain the tooth enamel as a calcified
deposit thereon. It can be that as the cationic or long chain
tertiary amine antibacterial agents remove plaque they also
denature protein from saliva in the oral environment and the
denatured protein can then act as a nucleating agent which is
deposited on and stains or discolors tooth enamel.
Previously employed additives which reduced dental staining by
cationic antibacterial antiplaque agents also generally reduced the
activity of the antibacterial agents or its ability to act on
dental plaque to measurable degrees. Further Victamide (also known
as Victamine C) which is the condensation product of ammonia with
phosphorus pentoxide actually increases staining even in the
absence of a cationic antibacterial antiplaque agent and it and
other known phosphorus containing agents such as
disodiumethane-1-hydroxy-1,1-diphosphonic acid salt precipitate in
the presence of antibacterial agent such as bis-biguanido compound,
thereby reducing the antiplaque effectiveness of the antibacterial
agent.
It is an advantage of this invention that an anti-nucleating
additive is provided which unexpectedly prevents staining of dental
enamel without precipitating or substantially adversely affecting
the antibacterial and antiplaque activity of cationic or long chain
tertiary amine antibacterial agents. Other advantages will be
apparent from consideration of the following disclosure.
In accordance with certain of its aspects, this invention relates
to an oral composition comprising an oral (orally acceptable)
vehicle, at least one cationic or long chain tertiary amine
antibacterial antiplaque agent which causes staining and, as
anti-staining additive, at least one water soluble oligomer of the
formula: ##STR4## wherein M is a water soluble orally acceptable
cation;
R.sub.1,r.sub.2,r.sub.3 and R.sub.4 are independently H, methyl or
ethyl;
Y is at least one hydrophilic member of the group consisting of
--COOM.sub.1, --CONH.sub.2, and --CH.sub.2 OH;
X is at least one hydrophobic member of the group consisting of
--CN, --COOR, --COOR.sub.5 OR, --CONHR, --COONHR.sub.5 COR, and
--OOCR;
M.sub.1 is H or M;
R is C.sub.1-8 alkyl;
R.sub.5 is C.sub.1-4 alkylene;
a is 0-7; and
a+b is about 4-15.
Oligomers of the above formula and methods for their production are
disclosed in U.S. Pat. Nos. 3,646,099 and 3,859,260, which
disclosures are incorporated herein by reference thereto. These
oligomers of relatively low and accurately regulated degree of
polymerization, [in contrast to the conventional free radical redox
polymerization conducted with an oxidative initiator such as
hydrogen, alkyl, or acyl peroxides, persulfates or hydroperoxides
in relatively large amounts and a reductive activator such as
NaHSO.sub.3, Na.sub.2 S.sub.2 O.sub.3,Na.sub.2 S.sub.2 O.sub.4 or
sodium formaldehyde sulfoxylate in relatively low amounts generally
added subsequently to the polymerization medium] are prepared by a
reductive polymerization in which a much larger amount of a
bisulfite salt, e.g. NaHSO.sub.3 (sodium bisulfite, sodium acid
sulfite), a reducing agent, is the initiator charged initially with
the monomer, and an oxidizing agent is added in smaller amounts as
the activator during the polymerizing or oligomerizing process.
Subscript a in formula I represents the number of moles of
hydrophobic groups, and subscript b the number of moles of
hydrophilic groups, in the oligomer molecule. The proportion of X
(i.e. the value of a) must be small enough, or even zero, to avoid
the production of a too large, sticky, and hydrophobic polymer
molecule, and will of course be dependent for the most part in any
particular instance on the identity of the X and Y groups, i.e. the
hydrophobic-containing and hydrophilic-containing monomeric
reactants. Mixtures of such oligomers may of course also be
employed.
Examples of monomers containing hydrophilic Y groups are acrylic
acid, methacrylic acid, alpha-ethylacrylic acid, beta-methylacrylic
acid, alpha, beta-dimethylacrylic acid, orally acceptable salts
(M.sub.1) of these acids, for example those containing such cations
as alkali metal (e.g. sodium and potassium), ammonium, C.sub.1-18
mono-, di- and tri- substituted ammonium (e.g. alkanol substituted
such as mono-, di- and tri-ethanol-ammonium), etc., acrylamide,
methacrylamide, ethacrylamide, and allyl alcohol and the like.
Examples of monomers containing hydrophobic X groups are
acrylonitrile, methacrylonitrile, ethacrylonitrile, methyl and
ethyl and octyl acrylate and methacrylate, methoxyethyl acrylate,
octoxyethyl methacrylate, ethoxybutyl methacrylate, propoxymethyl
acrylate, N-ethylacrylamide, N-isopropylacrylamide,
N-methylacrylamide, N-isooctylmethacrylamide,
N-propylethacrylamide, vinyl acetate, propionate and octanoate,
diacetone acrylamide and the like.
The oligomerization is carried out in water in the presence of a
relatively large amount of the bisulfite reducing initiator.
Generally, the amount of reducing initiator, expressed in mols of
monomer/gram formula weight (gFW) of reducing initiator is about 4
to 15, this ratio determining the degree of oligomerization.
The reductive initiator is preferably a water soluble bisulfite
salt, (M in formula I), especially alkali metal such as sodium or
potassium, but bisulfite salts containing other orally acceptable
cations of the type referred to above may be employed.
In practice, enough oxidative activator is used to effect 100%
conversion of the monomers to oligomers. The amount of such
activator, expressed as gFW activator/gFW initiator may range from
0.0001 to 0.1 but usually is from about 0.001 to 0.1. Examples of
these oxidative activators are ammonium, sodium and potassium
persulfate, hydrogen peroxide and other water soluble oxidants
commonly employed in the polymerization art.
Following completion of the oligomerization reaction, any free
carboxylic acid groups in the oligomer molecules may if desired be
partially or completely neutralized, preferably at least 60%, by
treating the aqueous oligomer solution with a suitable base to
convert such groups to their salts with orally acceptable cations
as referred to above. These aqueous oligomer solutions have a
highly desirable low viscosity, and low molecular weight range
depending on the monomer units in the oligomer.
It will be understood that Formula I above is not intended to
depict the actual structure of the oligomer molecule, the bracketed
units of which formula are randomly distributed in the molecule
with the --SO.sub.3 M group being normally bonded to a terminal
carbon atom in the oligomer chain devoid of X and or Y
substituents. In the oligomers preferred for use herein, a is zero,
Y is --COOM.sub.1, R.sub.1 -R.sub.4 are H, and M and M.sub.1 are
alkali metal, e.g. sodium, b being about 10, as derived from
acrylic acid. An oligomer of formula I above in the form of its
sodium salt, with a molecular weight of about 1,000, containing
about 10 acrylic acid monomeric units, is commercially available
under the trade name ND-2 (a product of UniRoyal).
U.S. Pat. No. 3,934,002, discloses among a number of alternative
compounds suggested for reducing the staining ordinarily caused by
bis-biguanide antiplaque agents, homopolymers and copolymers
containing units of the type present in the oligomer additives of
this invention. Such polymers however are devoid of the essential
sulfonic group of said oligomers, and are difficult to produce in
the low 4-15 unit range and low-viscosity properties attributable
to such oligomers. Such oligomers are further more advantageously
employed in the instant oral compositions by reason of their
water-solubilizing, water-dispersing sulfonic acid
substituents.
The concentration of these oligomer additives in oral compositions
can range widely, typically upward from about 0.01% by weight with
no upper limit except as dictated by cost or incompatibility with
the vehicle. Generally, concentrations of about 0.01% to about 10%
and preferably about 0.5% to 2% by weight are utilized. Oral
compositions which in the ordinary course of usage could be
accidentally ingested preferably contain lower concentrations of
these additives. Thus, a mouthwash in accordance with this
invention preferably contains less than about 1 weight % of the
additive. Dentrifice compositions, topical solutions and
prophylactic pastes, the latter to be administered professionally,
can preferably contain about 0.1 to 2 weight % of the additive.
Most desirably the oligomer additive is present in a molar ratio
relative to the amount of antibacterial antiplaque agent (based on
its free base form) of about 0.2:1 to about 6:1, preferably about
0.5:1 to about 4:1, in order to best minimize, inhibit or prevent
staining.
Nitrogen-containing antibacterial agents which are cationic or long
chain amine germicides which may be employed in the practice of
this invention are described above. They are typically employed in
amounts such that the oral product contains between about 0.001 and
15% by weight of the agent. Preferably for desired levels of
antiplaque effect, the finished oral product contains about 0.01 to
about 5%, and most preferably about 0.25 to 1.0% by weight of the
antibacterial agent, referring to its free base form.
The stain which generally occurs on dental enamel is unexpectedly
substantially or entirely prevented when the above-defined oligomer
additives or orally acceptable water soluble salts thereof, are
employed. These materials are anti-nucleating agents. In themselves
(even in the absence of cationic antiplaque antibacterial agents)
they are effective to reduce formation of dental calculus without
unduly decalcifying enamel. However, not all anti-nucleating agents
are effective to prevent stain by cationic antibacterial agents.
Victamide actually increases staining even in the absence of an
antibacterial antiplaque agent.
In certain highly preferred forms of the invention the oral
composition may be substantially liquid in character, such as a
mouthwash or rinse. In such a preparation the vehicle is typically
a water-alcohol mixture. Generally, the ratio of water to alcohol
is in the range of from about 1:1 to about 20:1 preferably from 3:1
to 20:1 and most preferably about 17:3, by weight. The total amount
of water alcohol mixture in this type of preparation is typically
in the range of from about 70 to about 99.9% by weight of the
preparation. The pH of such liquid and other preparations of the
invention is generally in the range of from about 4.5 to about 9
and typically from about 5.5 to 8. The pH is preferably in the
range of from about 6 to about 8.0. It is noteworthy that the
compositions of the invention may be applied orally at a pH below 5
without substantially decalcifying dental enamel.
Such liquid oral preparations may also contain a surface active
agent and/or a fluorine-providing compound.
In certain other desirable forms of this invention, the oral
composition may be substantially solid or pasty in character, such
as toothpowder, a dental tablet, a toothpaste or dental cream. The
vehicle of such solid or pasty oral preparations contains polishing
material. Examples of polishing materials are water-insoluble
sodium metaphosphate, potassium metaphosphate, tricalcium
phosphate, dihydrated calcium phosphate, anhydrous dicalcium
phosphate, calcium pyrophosphate, magnesium orthophosphate,
trimagnesium phosphate, calcium carbonate, alumina, hydrated
alumina, aluminum silicate, zirconium silicates, silica, bentonite,
and mixtures thereof. Preferred polishing materials include
crystalline silica having particle sizes of up to 5 microns, a mean
particle size of up to 1.1 microns, and a surface area of up to
50,000 cm.sup.2 /gm. silica gel, complex amorphorus alkali metal
aluminosilicate and hydrated alumina.
Alumina, particularly the hydrated alumina sold by Alcoa as C333,
which has an alumina content of 64.9% by weight, a silica content
of 0.008%, a ferric oxide content of 0.003%, and a moisture content
of 0.37 %, at 110.degree. C., and which has a specific gravity of
2.42 and a particle size such that 100% of the particles are less
than 50 microns and 84% of the particles are less than 20 microns,
is particularly desirable.
When visually clear gels are employed, a polishing agent of
colloidal silica, such as those sold under the trademark SYLOID as
Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel
100 and alkali metal aluminosilicate complexes are particularly
useful, since they have refractive indices close to the refractive
indices of gelling agent-liquid (including water and/or humectant)
systems commonly used in dentifrices.
Many of the so-called "water-insoluble" polishing materials are
anionic in character and also include small amounts of soluble
material. Thus, insoluble sodium metaphosphate may be formed in any
suitable manner, as illustrated by Thorpe's Dictionary of Applied
Chemistry, Volume 9, fourth Edition, pp. 510-511. The forms of
insoluble sodium metaphosphate known as Madrell's salt and Kurrol's
salt are further examples of suitable materials. These
metaphosphate salts exhibit a minute solubility in water, and
therefore are commonly referred to as insoluble metaphosphates.
There is present therein a minor amount of soluble phosphate
material as impurities, usually a few percent such as up to 4% by
weight. The amount of soluble phosphate material, which is believed
to include a soluble sodium trimetaphosphate in the case of
insoluble metaphosphate, may be reduced by washing with water if
desired. The insoluble alkali metal metaphosphate is typically
employed in powder form of a particle size such that no more than
about 1% of the material is larger than 37 microns.
The polishing material is generally present in amounts ranging from
about 20 to about 99% by weight of the oral preparation.
Preferably, it is present in amounts ranging from about 20 to about
75% in toothpaste, and from about 70 to about 99% in
toothpowder.
In the preparation of toothpowders, it is usually sufficient to
admix mechanically, e.g., by milling, the various solid ingredients
in appropriate quantities and particle sizes.
In pasty oral preparations the above-defined combination of the
antibacterial antiplaque agent and oligomer additive should be
compatible with the other components of the preparation. Thus, in a
toothpaste, the liquid vehicle may comprise water and humectant
typically in an amount ranging from about 10 to about 90% by weight
of the preparation. Glycerine, sorbitol, or polyethylene glycol may
also be present as humectants or binders. Particularly advantageous
liquid ingredients comprise mixtures of water, glycerine and
sorbitol.
In clear gels where the refractive index is an important
consideration, about 3-30% by weight of water, 0 to about 80% by
weight of glycerine, and about 20-80% by weight of sorbitol is
preferably employed. A gelling agent, such as natural or synthetic
gums or gum-like materials, typically Irish moss, sodium
carboxymethylcellulose, methyl cellulose, or hydroxyethyl
cellulose, may be employed. Other gelling agents which may be
employed include gum tragacanth, polyvinylpyrrolidone and starch.
They are usually present in toothpaste in an amount up to about 10%
by weight, preferably in the range of from about 0.5 to about 5%.
The preferred gelling agents are methyl cellulose and hydroxyethyl
cellulose. In a toothpaste or gel, the liquids and solids are
proportioned to form a creamy or gelled mass which is extrudable
from a pressurized container or from a collapsible, e.g., aluminum
or lead, tube.
The solid or pasty oral preparation which typically has a pH
measured on a 20% slurry of about 4.5 to 9, generally about 5.5 to
about 8 and preferably about 6 to about 8.0, may also contain a
surface active agent and/or a fluorine-providing compound.
It will be understood that, as is conventional, the oral
preparations are to be sold or otherwise distributed in suitable
labelled packages. Thus a jar of mouthrinse will have a label
describing it, in substance, as a mouthrinse or mouthwash and
having directions for its use; and a toothpaste will usually be in
a collapsible tube, typically aluminum or lined lead, or other
squeeze dispenser for metering out the contents, having a label
describing it, in substance, as a toothpaste or dental cream.
In oral compositions such as mouthrinses and toothpastes, a
surfactant is often present, e.g. to promote foaming. It will be
understood that it is preferable to employ nonionic surfactants
rather than their anionic counterparts. Examples of water-soluble
nonionic surfactants are condensation products of ethylene oxide
with various reactive hydrogen-containing compounds reactive
therewith having long hydrophobic chains (e.g. aliphatic chains of
about 12 to 20 carbon atoms), which condensation products
("ethoxamers") contain hydrophilic polyoxyethylene moieties, such
as condensation products of ethylene oxide with fatty acids, fatty
alcohols, and fatty amides, including alcohols such as sorbitan
monostearate or polypropyleneoxide (that is Pluronic
materials).
In certain forms of this invention a fluorine-providing compound is
present in the oral preparation. These compounds may be slightly
soluble in water or may be fully water-soluble. They are
characterized by their ability to release fluoride ions in water
and by substantial freedom from reaction with other compounds of
the oral preparation. Among these materials are inorganic fluoride
salts, such as soluble alkali metal, alkaline earth metal and heavy
metal salts, for example, sodium fluoride, potassium fluoride,
ammonium fluoride, lead fluoride, a copper fluoride such as cuprous
fluoride, zinc fluoride, a tin fluoride such as stannic fluoride or
stannous chlorofluoride, barium fluoride, sodium fluorsilicate,
ammonium fluorosilicate, sodium fluorozirconate, sodium
monofluorophosphate, aluminum mono- and di-fluorophosphate, and
fluorinated sodium calcium pyrophosphate. Alkali metal and tin
fluorides, such as sodium and stannous fluorides, sodium
monofluorophosphate and mixtures thereof, are preferred.
The amount of the fluorine-providing compound is dependent to some
extent upon the type of compound, its solubility, and the type of
oral preparation, but it must be a nontoxic amount. In a solid oral
preparation, such as toothpaste or toothpowder, an amount of such
compound which releases a maximum of about 1% by weight of the
preparation is considered satisfactory. Any suitable minimum amount
of such compound may be used, but it is preferable to employ
sufficient compound to release about 0.005 to 1%, and preferably
about 0.1% of fluoride ion. Typically, in the cases of alkali metal
fluorides and stannous fluoride, this component is present in an
amount up to about 2% by weight, based on the weight of the
preparation, and preferably in the range of about 0.05 to 1%. In
the case of sodium monofluorophosphate, the compound may be present
in an amount up to 7.6% by weight, more typically about 0.76%.
In a liquid oral preparation such as a mouthwash, the
fluorine-providing compound is typically present in an amount
sufficient to release up to about 0.13%, preferably about 0.0013 to
0.1% and most preferably about 0.0013 to 0.05%, by weight, of
fluoride ion.
Various other materials may be incorporated in the oral
preparations of this invention. Examples are whitening agents,
preservatives, silicones, chlorophyll compounds, and ammoniated
material such as urea, diammonium phosphate, and mixtures thereof.
These adjuvants, where present, are incorporated in the
preparations in amounts which do not substantially adversely affect
the properties and characteristics desired.
Any suitable flavoring or sweetening material may also be employed.
Examples of suitable flavoring constituents are flavoring oils,
e.g., oils of spearmint, peppermint, wintergreen, sassafras, clove,
sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl
salicylate. Suitable sweetening agents include sucrose, lactose,
maltose, sorbitol, sodium cyclamate, perillartine, and saccharine.
Suitably, flavor and sweetening agents may together comprise from
about 0.01 to 5% or more of the preparation.
In preparing the oral compositions of this invention comprising the
above-defined combination of antibacterial agent and oligomer
additive in an oral vehicle which typically includes water, it is
highly preferred if not essential to add the oligomer after the
other ingredients (except perhaps some of the water) are mixed or
contacted with each other to avoid a tendency for said agent to be
precipitated.
For instance, a mouthrinse or mouthwash may be prepared by mixing
ethanol and water with flavoring oil, nonionic surfactant,
humectant, cationic antibacterial antiplaque agent, such as
benzethonium chloride or chlorohexidine, sweetener, color and then
the above-defined oligomer additive, followed by additional water
as desired.
A toothpaste may be prepared by forming a gel with humectant, gum
or thickener such as hydroxyethyl cellulose, sweetener and adding
thereto polishing agent, flavor, antibacterial agent, such as
benzethonium chloride or chlorhexidine, additional water, and then
the above-defined oligomer additive. If sodium carboxymethyl
cellulose is employed as the gelling agent the procedure of either
U.S. Pat. No. 3,842,168 or U.S. Pat. No. 3,843,779, modified by the
inclusion of the oligomer additive, is followed.
In the practice of this invention an oral composition according to
this invention such as a mouthwash or toothpaste containing
cationic or long chain amine antibacterial antiplaque agent in an
amount effective to promote oral hygiene and the defined oligomer
additive in an amount effective to reduce staining of dental
surfaces otherwise resulting from the presence of the antibacterial
antiplaque agent, is applied regularly to dental enamel, preferably
from about 5 times per week to about 3 times daily, at a pH of
about 4.5 to about 9, generally about 5.5 to about 8, preferably
about 6 to 8.
The following specific examples are further illustrative of the
nature of the present invention, but it is understood that the
invention is not limited thereto. All amounts and proportions
referred to herein and in the appended claims are by weight unless
otherwise indicated.
EXAMPLE A
The procedure of Example 1 of U.S. Pat. No. 3,646,099 is followed,
the initial charge to the reactor being 3.12g NaHSO.sub.3 (0.03
gFW), 159.8g. water, and 20.74g. acrylic acid (0.288 mol) as the
sole monomer, a correspondingly equivalent amount of the
(NH.sub.4).sub.2 S.sub.2 O.sub.8 activator being employed. The
ratio of mols of monomer to gFW NaHSO.sub.3 is 9.6, and the
oligomer, fully neutralized with 5NNaOH at the completion of the
reaction, may be represented by the formula ##STR5##
In this case, a in formula I above is zero and b is 9.6 (average).
A clear solution is obtained, this Oligomer A having a molecular
weight of about 1,000.
EXAMPLE 1
Inhibition of Crystal Growth of HAP
This is evaluated by a pH Stat method. 1.0 ml of 0.1M sodium
dihydrogen phosphate is placed in a reaction flask with 22 to 23
ml. of distilled water with continuous stirring in an atmosphere of
nitrogen. To this is added 1 ml. of 0.1M CaCl.sub.2 and the pH
adjusted to 7.4.+-.0.05 (final conc. of Ca.sup.++ and
PO.sub.4.sup.3- -4.times.10.sup.-3 M). Consumption of 0.1MNaOH is
recorded automatically by a pH Stat (Radiometer). In this test, the
formation of HAP occurs in 2 distinct phases. First rapid base
consumption (1-4 min.) then diminishes until 15-20 minutes when
second rapid uptake takes place. A delay in the time of second
rapid consumption or a total absence of the second rapid
consumption indicates an interference with the crystal growth of
HAP. Agents which interfere with HAP crystal growth are effective
anticalculus agents. When subjected to the foregoing procedure,
Oligomer A above is found to delay the formation of the second
phase by more than 12 hours, while Acrysol A-5 polyacrylic acid and
sodium polyacrylic acid have no affect.
It is thus clear that Oligomer A effectively inhibits the crystal
growth of HAP and that the inhibition is not merely due to the
complexation or chelation of calcium from the system since the
ratio of inhibitor to total calcium is 1:40 to 1:80.
In the following examples, BC refers to benzethonium chloride, and
Pluronic F108 is a polyalkene oxide block polymer.
TABLE I ______________________________________ MOUTHWASH
FORMULATIONS (1) (2) Example Placebo Control (3) (4) (5)
______________________________________ Flavor 0.22% 0.22% 0.22%
0.22% 0.22% Ethanol 15.0 15.0 15.0 15.0 15.0 Pluronic F108 3.0 3.0
3.0 3.0 3.0 Glycerine 10.0 10.0 10.0 10.0 10.0 Na saccharin 0.03
0.03 0.03 0.03 0.03 BC -- 0.075 0.075 0.075 0.075 Oligomer A -- --
0.1 0.2 0.5 Water q.s. to 100 100 100 100 100 pH(with NaOH) 7.4 7.4
7.4 7.4 7.4 Appear- ance Clear Clear Clear Clear Clear Reflect-
ance 55.0 46.0 53.0 54.0 54.0 Reflect- ance Dif- ference -- -- 7.0
8.0 8.0 ______________________________________
The Oligomer A and about 10 parts of the water are added to the
other previously mixed ingredients. Tooth staining characteristics
are tested by slurrying hydroxyapatite (Biogel) with salivary
protein, acetaldehyde (as carbonyl source) and a pH7 phosphate
buffer. The mixture is shaken at 37.degree. C. until a light brown
color is formed. Colored powder is separated by filtration, dried
and color levels (in reflectance units) determined on a Gardner
color difference meter before and after the test formulation is
applied to the colored material.
The above results plainly establish that the oligomer additives of
the present invention, as exemplified by Oligomer A, substantially
reduce dental staining ordinarily produced by quaternary ammonium
antibacterial antiplaque agents as exemplified by BC. Formulations
adjusted to pH5-8 yield similar results. Other orally acceptable
salts of Oligomer A yield similar results.
Further, In vitro tests for antiplaque activity against a preformed
plaque on teeth (induced by Actinomyces viscosus) establish the
formulation of Example 2 (0.075%BC) and a similar formulation also
containing 1.0% of Oligomer A to be substantially equal, indicating
that these oligomer additives do not significantly affect the
antiplaque activity of BC and the like.
Substitution of equivalent amounts of the following antibacterial
antiplaque agents for the BC employed in Examples 3-5 yield
formulations also producing unexpected reductions in dental
staining:
______________________________________ Example Antibacterial
Antiplaque Agent ______________________________________ 6
chlorhexidine diacetate 7 chlorohexidine digluconate 8 dodecyl
trimethyl ammonium bromide 9 cetyl pyridinium chloride 10 ##STR6##
11 alexidine dihydrochloride The following formulations exemplify
toothpastes with antiplaque activity and reduced staining:
______________________________________ Example (Parts) 12 13
______________________________________ Hydrated alumina 30 30
Glycerine 16 16 Sorbitol (70%) 6 6 Pluronic F-108 3 3 Hydroxyethyl
cellulose 1.2 1.2 Benzethonium chloride (BC) 0.5 -- Chlorhexidine
digluconate (20%) -- 4.725 Oligomer A 2 2 Sodium saccharin 0.17
0.17 Flavor 0.8 0.8 Water q.s. to 100 100
______________________________________
Significant reductions in dental staining are also obtained
according to the present invention when Oligomer A in the above
examples is replaced by any of the co-oligomers prepared by the
procedures of Examples I-XIII of U.S. Pat. Nos. 3,646,099 and
3,859,260 suitably adjusted to yield a co-oligomer of formula I
above in which a is 0-7 and a+b is about 4-15.
This invention has been described with respect to preferred
embodiments and it will be understood that modifications and
variations thereof obvious to those skilled in the art are to be
included within the spirit and purview of this application and the
scope of the appended claims.
* * * * *